1. Field of the Invention
The present invention relates to a method of treating hypertension in human by orally administering an effective amount of methylreserpate of the formula (I): ##STR1##
The invention also relates to a pharmaceutical composition for treating hypertension in human. The composition comprises the above mentioned methylreserpate as the active ingredient and any other additive or excipient for oral administration.
2. State of the Art
Hypertension, along with cancer and heart disease, is one of the typical adult diseases and, as the number of aged persons increases so does the number of hypertensitive patients. Though therapy for hypertension is a very important problem, for various reasons no decisive method of treatment has been established.
Reserpine (hereinafter referred to as "RSP") and Rescinnamin (hereinafter referred to as "RCN"), which are Rauwolfia alkaloids, have long been used as remedies for hypertension because of their prolonged antihypertensive effect. However, their use is accompanied by unpleasant side effects such as uneasiness due to central nervous system depression, depressed state and loss of vitality. Thus, clinicans have been seeking RSP-type antihypertensive agents with little or no central nervous system depressive effect.
Methylreserpate (hereinafter referred to as "MR") was found in Rauwolfia Serpentina by Hoffmann et al. in 1954 [Helv. Chim. Acta., 37, 849 (1954)], and widely known as a metabolite of RSP [Dhar, M. M. et al.: J. Sci. Ind. Res., 140, 179 (1955); Glazko, A. J. et al.: J. Pharmacol. Exp. Therap., 118, 377 (1956); Dhar, M. M. et al.: Indian J. Pharmacy, 18, 293 (1956); Maggiolo, C. et al.: Proc. Soc. Exp. Biol. Med., 115, 149 (1964); and Huebner, C. F. et al.: J. Amer. Chem. Soc., 77, 469 (1955)].
Some researches were made on biologicl activity of this compound, and the following reports were made:
The substance exhibited no antihypertensive effect [Dhar, M. M. et al.: J. Sci. Ind. Res., 140, 179 (1955); Dhar, M. M. et al.: Indian J. Pharmacy, 18, 293 (1956); Bein, H. J.: Pharmacol. Rev., 8, 435 (1956); and Huebner, C. F. et al.: J. Amer. Chem. Soc., 77, 469 (1955)].
Inhibitory action of central nervous system was less than that of RSP [Dhar, M. M. et al.: J. Sci. Ind. Res., 140, 179 (1955); Indian J. Pharmacy, 18, 293 (1956); Bein, H. J.: Pharmacol. Rev., 8, 435 (1956); Huebner, C. F. et al.: J. Amer. Chem. Soc., 77, 469 (1955); Rubin, B. et al.: Fed. Proc., 13, 400 (1954); Dasgupta, S. R. et al.: Brit. J. Pharmacol., 12, 529 (1957); and Plummer, A. J. et al.: Fed. Proc., 13, 395 (1954)]. There was observed no decrease of serotonin in Brain [Brodie, B. B. et al.: Science, 123, 992 (1956)], increse of histamine [Sachdev, K. S. et al.: Arch. int. Pharmacodyn. Ther., 157, 14 (1965)] and slight decrease of noradrenaline in heart and adrenals [Creveling, C. R. et al.: J. Med. Chem. 11, 596 (1968)].
We investigated and confirmed first of all that MR is readily absorbed in the digestive tract. Then, based on our detailed study of the antihypertensive effect of MR on spontaneously hypertensive rats (SHR) and dogs, we have found that orally administered MR exhibits prolonged antihypertensive effect, and, though mild, has sufficient antihypertensive therapeutic activity. Finally, we investigated the toxicity and metabolism of MR, and confirmed that MR can be safely used as an antihypertensive medicine with little risk of central nervous system depression.